Multiple Myeloma and Related Plasma Cell Disorders Flashcards
Define multiple myeloma.
Malignancy of BM plasma cells, the terminally differentiated + immunoglobulin (Ig) secreting B cells.
List 4 actions of myeloma plasma cells.
Home + infiltrate BM
May form bone expansile or soft tissue tumours: Plasmacytomas
Produce a serum monoclonal IgG or IgA: Paraprotein or M-spike
Produce excess of monoclonal (κ or λ) serum free light chains
Bence-Jones protein: Urine monoclonal free light chains
7 epidemiological facts of multiple myeloma.
2nd most common haematological malignancy, 19th in all cancers.
Median age 67y.
Incidence increases with age.
1% <40y
M > F
Black > Caucasian + Asians.
Prevalence of myeloma increasing
Explain the aetiology/ risk factors of multiple myeloma.
Aetiology is unknown.
Risk factors:
Obesity
Age
Genetics: Incidence in black population + sporadic cases of familiar myeloma
What is multiple myeloma always preceeded by?
A premalignant condition:
Monoclonal Gammopathy of Uncertain Significance (MGUS)
Summarise the epidemiology of MGUS.
Incidence increases with age
Up to 1% - 3.5% in elderly
Average risk for progression: 1% annually (most don’t)
In MGUS, which Ig antibodies predispose for myeloma?
IgG
IgA
What does IgM MGUS progress to?
Lymphoma
What is MGUS associated with?
Osteoporosis
Thrombosis
Bacterial infection
What is the WHO diagnostic criteria for MGUS?
Serum M-protein <30g/L
BM clonal plasma cells <10%
No lytic bone lesions
No myeloma-related organ or tissue impairment
No evidence of other B-cell proliferative disorder
What are risk factors for MGUS?
Non-IgG M-spike
M-spike >15g/L
Abnormal serum free light chain (FLC) ratio
Which 2 criteria define smouldering multiple myeloma?
Serum monoclonal protein (IgG or IgA) >30g/L or urinary monoclonal protein >500mg per 24h +/- clonal BM plasma cells 10-60%.
Absence of myeloma defining events or amyloidosis.
What are risk factors for smouldering multiple myeloma?
BM myeloma cells ≥20%
M-spike ≥20g/L
Serum FLC ratio ≥20
>2 RFs = high risk
What is the general course for multiple myelome and related plasma cell disorders?
- MGUS
- Smouldering myeloma
- Symptomatic myeloma
- Remitting-relapsing
- Refractory
- Plasma cell leukaemia
How does multiple myeloma affect the bone marrow microenvironment?
Bone destruction
Anaemia
Angiogenesis
Immunosuppressants + infections
How is multiple myeloma diagnosed?
≥10% plasma cells in BM
or
Plasmacytoma + ≥1 CRAB or MDE
What is CRAB?
C: Hypercalcaemia: Calcium >2.75mmol/L
R: Renal disease: Creatinine >177μmol/L or eGFR <40ml/min
A: Anaemia: Hb <100g/L or drop by 20g/L
B: Bone disease: >,1 bone lytic lesion on imaging
What is MDE?
Myeloma Defining Events (MDE)
BM plasma cell pop. high ≥60%
Involved: Uninvolved FLC ratio >100
> 1 focal lesion in MRI (>5mm)
What is the association between myeloma and bone disease?
80% myeloma patients present with bone disease
6 features of clinical presentation in multiple myeloma patients?
Proximal skeleton
Back (spine), chest wall + pelvic pain
Osteolytic lesions, never osteoblastic
Osteopenia
Pathological fractures
Hypercalcaemia
What are emergencies associated with bone disease in multiple myeloma patients?
Cord compression:
Dx + Tx within 24h
MRI scan
Ig + FLC studies +/- biopsy
Dexamethasone
Radiotherapy
Neurosurgery: rarely required
Stabilise unstable spine
MDT meeting
Hypercalcaemia:
Presents with drowsiness, constipation, fatigue, muscle weakness, AKI
Fluids, steroids, zolendronic acid
Define myeloma kidney disease.
Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI)
AKI resulting from myeloma.
What are causes of myeloma kidney disease?
Cast nephropathy is caused by high SFLC levels + Bence Jone proteinuria.
Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics.
20-50% AKI at dx.
2-4% of newly diagnosed require dialysis.
What is the association with myeloma kidney disease and prognosis of multiple myeloma?
12% early death
Prolonged hospital stay + lethal infections
Why is multiple myeloma associated with immunodeficiency?
Immunoparesis: Low serum normal Igs
Myeloid, T cells + NK cells impairment
Chemotherapy impairs immune response
Myeloma immune evasion
What is the diagnostic workup for multiple myeloma?
Immunoglobulin studies:
Serum protein electrophoresis
Serum FLC levels
24h Bence Jones protein
BM aspirate + biopsy: IHC for CD138
FISH analysis: Should include at least high risk abnormalities
Flow cytometry immunophenotyping
What are common target organs of AL amyloidosis?
Kidney
Heart
Liver
Neuropathy
What are 5 signs and symptoms of AL amyloidosis?
Nephrotic syndrome 70%: Proteinuria (not BJP!), peripheral oedema
Unexplained HF → determinant of prognosis: Raised NT-proBNP, Abnormal echocardiography + cardiac MRI
Sensory neuropathy
Abnormal LFTs
Macroglossia
What is Monoclonal Gammopathy of Renal Significance (MGRS)?
Applies specifically to any B-cell clonal lymphoproliferation where there are:
- >,1 kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig).
- The underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy.
What is the pathophysiology of MGRS?
Rare disease, several subtypes
Demonstration of the involved monoclonal Ig or light chain possible in most cases
Work up similar to myeloma
Many require myeloma-type tx aiming to improve renal survival
Many lose kidney function
Which drugs have been used for a long time in myeloma therapy?
Cytostatic drugs: Melphalan, Cyclophosphamide
Immunomodulatory drugs: Thalidomide, Lenalidomide
Steroids: Dexamethasone + Prednisolone
Why are proteasome inhibitors useful in multiple myeloma?
Myeloma cells are protein production factories- all proteins made folded in ER.
Proteasome degrades misfolded protein
Causes accumulation of misfolded protein, ER stress + apoptosis
ER associated degradation (ERAD)
What are some proteasome inhibitors used in the treatment of myeloma?
Bortezomib
Approved for first line or relapse
IV or S/C
Neuropathy is main toxicity
Carfilzomib
More potent than Bortezomib
Approved in relapse
IV only
Thrombocytopenia, cardiotoxicity
Ixazomib
Approved in relapse, in combination
Oral
Favourable toxicity profile
Describe the pathogenesis of multiple myeloma
Primary event: Hyperdiploidy (60%) / IgH rearrangements
Secondary event: KRAS, NRAS, MYC
Which is the most common cytogenetic abnormality in myeloma?
Hyperdiploid karyotype
How does AL amyloidosis arise?
MGUS or myeloma in background
Misfolded SFLCs aggregate into amyloid fibrils in target organs
Amyloidogenic potential of FLC more important than amount
How may Amyloid fibrils be recognised?
Stain with Congo Red
Solid, non-branching + randomly arranged
Name a key histopathological myeloma marker
CD138
Name 2 anti-CD38 moAbs and state their MOA
Daratumumab
Isatuximab
Binds CD38 on MM cells
Initiates complement cascade → cell death
Binds CTL + Macrohages → cell death
Crosslinking → Apoptosis
What type of response has the best prognosis, and thus is what treatment aims for?
Complete response, minimal residual disease negative (MDR -ve)
Complete response alone is not enough, as MDR +ve patients have worse outcome
Name 3 emerging therapeutic agents entering myeloma standard of care
CAR T-cell therapy
BiTE
Immunoconjugates: brings together tumour cell + effector T cell, stimulates T cell to kill tumour cell
Why are steroids used in multiple myeloma?
Induce apoptosis in myeloma cells
Strong synergy, part of almost all combination regimens
Describe the use of Melphalan in multiple myeloma
Autologous Haematopoietic Stem Cell Transplant
- Stem cells harvested from blood + stored
- High dose Melphalan used to kill myeloma cells (alkylating agent→X-links)
- Re-infusion of stem cells to rescue blood formation
Describe the use of Thalidomide in multiple myeloma
Targets the turnover of transcription factors that are key to myeloma cell survival
